Alzheimer's Disease is a progressive neurodegenerative disorder that leads to the death of brain cells that cannot be replaced once lost. The neuropathology is characterized by the presence of amyloid plaques, neurofibrillary tangles, synaptic loss and selective neuronal cell death. The plaques are a result of abnormal levels of extracellular amyloid beta peptide (Aβ) while the tangles are associated with the presence of intracellular hyperphosphorylated tau protein. Symptoms first manifest clinically with a decline in memory followed by deterioration in cognitive function and normal behavior. Age is the single most prominent risk factor with the incidence doubling every five years from at the age of 65. Prevalence studies estimated that in 2000 the number of persons with AD in the US alone was 4.5 million with numbers expected to increase almost 3 fold in the next 50 years due to the rapid growth of the oldest age groups. The increasing number of dementia patients in the developed world will place an enormous burden on society and the health care systems.
Despite significant advances in the understanding of AD pathogenesis there are no drugs that exhibit profound disease-modifying effects. Although great efforts are being made to develop future classes of drugs to slow disease progression, current therapy, typified by the acetylcholinesterase inhibitors, is mainly limited to alleviating symptoms (Davis R E et al. (1995) Arzneimittelforschung, 45:425-431). Early diagnosis is a prerequisite for early treatment and will be of even greater significance if drugs aimed at slowing neurodegeneration show a clinical effect.
Current criteria for the clinical diagnosis of AD are largely dependent on the exclusion of other dementias and include neuropsychological testing and neuroimaging, where possible (McKhann G. et al., (1984) Neurology 34:939-944). Although reasonably high accuracy rates of 80-90% using clinical criteria have been reported (Kosunen O et al., (1996) Acta Neuropathol 91:185-193) these studies have been conducted by specialized centers typically diagnosing patients in the later stages of disease. Diagnostic accuracy within routine clinical practice is probably much lower, particularly during mild or pre-symptomatic stages of the disease. An unambiguous diagnosis of the disease is currently only possible by examination of brain tissue pathology and is not a clinically feasible process.
Several candidate biomarkers have been discovered in cerebrospinal fluid (CSF) such as Aβ1-42 and tau, which are the major components of amyloid plaques and neurofibrillary tangles, respectively. These tests have been commercialized and are used routinely in parts of Europe for research and diagnostic purposes. The diagnostic performance of these biomarkers is not optimal, however, especially with respect to specificity against other dementias (Blennow K & Hampel H, (2003) Lancet Neurol. 2:605-613). Many other markers have been proposed in both serum and CSF and include amyloid precursor protein, apoE, isoprostanes (markers of lipid oxidation) and homocysteine. Whether these can be used as diagnostic markers has yet to be confirmed (Frank R A. et al. (2003) Neurobiol of Aging 24:521-536).
Therefore, there is an unmet need for simple biochemical tests that can detect AD at an early stage, monitor progression of the disease, and discriminate between AD, normal subjects, non-AD dementias and other neurological disorders.